Anti-bacterial vaccines are known in the art and examples include Haemophilus influenzae B vaccine which consists of bacterial polysaccharide conjugated with tetanus toxoid protein. Killed bacterial vaccines for the prophylaxis or treatment of enteric infections have also been known for some time and a killed bacterial vaccine for typhoid fever is commercially available. These vaccines are predominantly if not exclusively administered by injection and serve as “classic” vaccines in that they aim to stimulate a systemic antibody response to provide protection against disease.
Antigen administered orally is processed by gut-associated lymphoid tissue (GALT) differently from systemic lymphoid tissue. Teleologically, this can be understood in terms of mucosal physiologically where environmental “antigen” needs to be excluded but not at the cost of damaging mucosal “inflammation”. A powerful suppression mechanism therefore exists, to minimize potentially damaging immune responses to such antigen. This concept was originally identified as “split tolerance” where a systemic immune response (ie. mediated by the generation of antibody) was associated with the failure to detect a mucosal antibody response (tolerance). Research using orally administered killed influenza virus shows that an antibody response is stimulated over a narrow range of antigen dose. This immunization “zone” is flanked by low and high “zone” tolerance. The same concept applies to cellular immunity though the zone in which T-lymphocyte-mediated responses may be stimulated appears to be marginally wider with protection occurring without an antibody response. The outcome of antigen interaction with GALT is the selective migration of B and T-lymphocytes to distant mucosal sites of infection where they mediate protection.
An oral killed bacterial vaccine against infection by non-typeable Haemophilus influenzae (NTHi) is also known in the art. NTHi is the bacteria most commonly linked with nasal and bronchus colonization in subjects with chronic lung disease, and has been linked to acute episodes of bronchitis in these subjects. A significant factor in the generation of acute bronchitis in such subjects is the uncontrolled and inappropriate migration of neutrophils into the bronchus lumen in response to the colonizing bacteria. The accumulation of neutrophil-laden fluid within the bronchi results in purulent sputum. The use of the oral NTHi killed bacterial vaccine has been shown to protect against purulent sputum production, high levels of bacterial colonization of the airways and environmental spread of the bacteria as assessed by acquisition of infection by bystander subjects. The NTHi vaccine stimulates the common mucosal system following activation of GALT and more specifically, Peyer's patches in the intestines.
Oral non-adjuvenated monobacterial vaccines comprising killed bacteria for providing mucosal immunity particularly in patients with long term chronic lung disease are described in international patent application No. PCT/AU86/00071. Specifically, the application indicates that the immunization efficacy of the vaccine arises from the absence of adjuvant, which would normally be included in such vaccine formulations to promote an immune response. The generation of the immune response in the absence of the adjuvant was reasoned to be due to the response elicited by the killed bacteria being insufficient to trigger dominant suppressor T-cell populations in the lungs of the patients evaluated.